NO AND OXIDATIVE STRESS IN HUMAN MYOCARDIAL FAILURE

该项目的总体目标是确定心脏一氧化氮(NO)和氧化应激在人类心力衰竭(CHF)中的功能意义。最近的证据表明，在衰竭的人类心肌中，NO增加，可能参与了CHF的病理生理过程。此外，心力衰竭患者的心肌氧化应激增加。体外研究表明，活性氧(ROS)可对心肌产生直接毒性作用，与心肌收缩功能受损、胎儿基因表达和细胞死亡有关。此外，在动物模型中，抗氧化剂已被证明可以减弱ROS的负性变力作用，并防止心力衰竭的发展。在左心室(LV)衰竭中，心率介导的收缩能力(力-频率关系)的增加减弱、平坦甚至倒置。虽然心动过速时未能增加收缩能力可能是导致CHF患者心输出量反应减少和运动耐量降低的原因之一，但其潜在的机制尚不清楚。在具体目标1中，我们将通过测量冠脉内注射一氧化氮合酶抑制剂NG-单甲基-L-精氨酸前和冠脉内注射一氧化氮合酶抑制剂时随着心率增加而发生的左室压上升峰值速率(dp/dt)的变化，来检验心肌一氧化氮合酶活性增加减弱左心衰患者的力-频率关系的假说。在特定的目标2中，我们将通过测定冠状动脉内注射抗氧化剂抗坏血酸之前和期间的力-频率关系来检验这一假设，即增加的心肌氧化应激减弱了左心衰患者的力-频率关系。AIMS 1和AIMS 2是评估心肌NO和氧化应激在心力衰竭中的急性功能意义的侵入性方案。在具体目标3中，我们将通过测量扩张型心肌病患者在心房起搏心动过速和冠状动脉内注射多巴酚丁胺期间的左心室收缩末期弹性来测试一种新的非侵入性系统检测收缩状态急性变化的能力。如果我们证明这项新技术能够在导管术实验室中测量收缩性能的变化，我们将通过测量收缩性心力衰竭患者在使用抗氧化剂和/或消炎剂治疗前后的收缩末期弹性来评估其检测左室性能慢性变化的能力。

The overall goal of this project is to determine the functional significance of myocardial nitric oxide (NO) and oxidative stress in humans with heart failure (CHF). Recent evidence suggests that NO is increased in failing human myocardium and may contribute to the pathophysiology of CHF. In addition, increased myocardial oxidative stress has been demonstrated in heart failure. In vitro studies indicate that reactive oxygen species (ROS) can exert direct toxic effects on the myocardium associated with impaired contractility, fetal gene expression and cell death. Moreover, antioxidants have been shown to attenuate the negative inotropic effects of ROS and prevent the development of heart failure in animal models. In left ventricular (LV) failure, the heart rate- mediated increase in contractility (force-frequency relationship) is attenuated, flat or even inverted. While the failure to increase contractility with tachycardia likely contributes to the reduced cardiac output response and exercise intolerance observed in patients with CHF, the underlying mechanisms are poorly understood. In Specific Aim 1, we will test the hypothesis that increased myocardial NO synthase (NOS) activity attenuates the force- frequency relationship in humans with LV failure by measuring the changes in the peak rate of rise of LV pressure (+dP/dt) that occur with increasing heart rates before and during intracoronary infusion of NG-monomethyl-L-arginine, an inhibitor of NOS. In Specific Aim 2, we will test the hypothesis that increased myocardial oxidative stress attenuates the force-frequency relationship in humans with LV failure by determining the force- frequency relationship before and during intracoronary infusion of the antioxidant ascorbic acid. Aims 1 and 2 are invasive protocols that will assess the acute functional significance of myocardial NO and oxidative stress in heart failure. In Specific Aim 3, we will test the ability of a novel, non-invasive system to detect acute changes in contractile state by measuring LV end-systolic elastance during atrial pacing tachycardia and intracoronary dobutamine infusion in patients with dilated cardiomyopathy. If we show that this new technology is able to measure changes in contractility in the catheterization laboratory, we will assess its ability to detect chronic changes in LV performance by measuring end-systolic elastance before and after therapy with antioxidants and/or anti- inflammatory agents in patients with systolic heart failure.